We have a suspicion that you are an automated web bot software, not a real user. To keep our site fast for other users, we have slowed down this page. The slowdown will gradually disappear. If you think this is a mistake, please contact us at genome-www@soe.ucsc.edu. Also note that all data for hgGeneGraph can be obtained through our public MySQL server and all our software source code is available and can be installed locally onto your own computer. If you are unsure how to use these resources, do not hesitate to contact us.
UCSC Genome Browser Gene Interaction Graph
Gene interactions and pathways from curated databases and text-mining
J Biol Chem 2011, PMID: 21471201

Cancer cell survival following DNA damage-mediated premature senescence is regulated by mammalian target of rapamycin (mTOR)-dependent Inhibition of sirtuin 1.

Back, Jung Ho; Rezvani, Hamid Reza; Zhu, Yucui; Guyonnet-Duperat, Véronique; Athar, Mohammad; Ratner, Desiree; Kim, Arianna L

DNA-damaging agents can induce premature senescence in cancer cells, which contributes to the static effects of cancer. However, senescent cancer cells may re-enter the cell cycle and lead to tumor relapse. Understanding the mechanisms that control the viability of senescent cells may be helpful in eliminating these cells before they can regrow. Treating human squamous cell carcinoma (SCC) cells with the anti-cancer compounds, resveratrol and doxorubicin, triggered p53-independent premature senescence by invoking oxidative stress-mediated DNA damage. This process involved the mTOR-dependent phosphorylation of SIRT1 at serine 47, resulting in the inhibition of the deacetylase activity of SIRT1. SIRT1 phosphorylation caused concomitant increases in p65/RelA NF-κB acetylation and the expression of an anti-apoptotic Bfl-1/A1. SIRT1 physically interacts with the mTOR-Raptor complex, and a single amino acid substitution in the TOS (TOR signaling) motif in the SIRT1 prevented Ser-47 phosphorylation and Bfl-1/A1 induction. The pharmacologic and genetic inhibition of mTOR, unphosphorylatable S47A, or F474A TOS mutants restored SIRT1 deacetylase activity, blocked Bfl-1/A1 induction, and sensitized prematurely senescent SCC cells for apoptosis. We further show that the treatment of UVB-induced SCCs with doxorubicin transiently stabilized tumor growth but was followed by tumor regrowth upon drug removal in p53(+/-)/SKH-1 mice. The subsequent treatment of stabilized SCCs with rapamycin decreased tumor size and induced caspase-3 activation. These results demonstrate that the inhibition of SIRT1 by mTOR fosters survival of DNA damage-induced prematurely senescent SCC cells via Bfl-1/A1 in the absence of functional p53.

Diseases/Pathways annotated by Medline MESH: Carcinoma, Squamous Cell
Document information provided by NCBI PubMed

Text Mining Data

sirtuin 1 ⊣ mammalian target of rapamycin (mTOR): " Cancer cell survival following DNA damage mediated premature senescence is regulated by mammalian target of rapamycin (mTOR) dependent Inhibition of sirtuin 1 "

SIRT1 → mTOR: " This process involved the mTOR dependent phosphorylation of SIRT1 at serine 47, resulting in the inhibition of the deacetylase activity of SIRT1 "

SIRT1 ⊣ mTOR: " The pharmacologic and genetic inhibition of mTOR , unphosphorylatable S47A, or F474A TOS mutants restored SIRT1 deacetylase activity, blocked Bfl-1/A1 induction, and sensitized prematurely senescent SCC cells for apoptosis "

Manually curated Databases

  • IRef Biogrid Interaction: SIRT1 — MTOR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: RPTOR — SIRT1 (physical association, affinity chromatography technology)
  • IRef Intact Interaction: Complex of MTOR-RPTOR-SIRT1 (association, anti bait coimmunoprecipitation)
  • IRef Intact Interaction: SIRT1 — MTOR (phosphorylation reaction, protein kinase assay)
  • IRef Intact Interaction: RPTOR — SIRT1 (physical association, anti bait coimmunoprecipitation)
In total, 3 gene pairs are associated to this article in curated databases